Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart

To determine the effects of age on the myocardium, the functional and structural characteristics of the heart were studied in rats at 4, 12, 20, and 29 months of age. Mean arterial pressure, left ventricular pressure and its first derivative (dP/dt), and heart rate were comparable in rat groups up to 20 months. During the interval from 20 to 29 months, elevated left ventricular end-diastolic pressure and decreased dP/dt indicated that a significant impairment of ventricular function occurred with senescence. In the period between 4 and 12 months, a reduction of nearly 19% in the total number of myocytes was measured in both ventricles. In the subsequent ages, similar decreases in myocyte cell number were found in the left ventricle, whereas in the right ventricle, the initial loss was fully reversed by 20 months. Moreover, from 20 to 29 months, a 59% increase in the aggregate number of myocytes occurred in the right ventricular myocardium. In the left ventricle, a 3% increment was also seen, but this small change was not statistically significant. These estimations of myocyte cellular hyperplasia, however, were complicated by the fact that cell loss continued to take place with age. The volume fraction of collagen in the tissue, in fact, progressively increased from 8% and 7% at 4 months to 16% and 22% at 29 months in the left and right ventricles, respectively. In conclusion, myocyte cellular hyperplasia tends to regenerate the ventricular mass being lost with age in the adult mammalian rat heart.     

Tissue-level inflammation and ventricular remodeling in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common cardiac condition caused primarily by sarcomeric protein mutations with several distinct phenotypes, ranging from asymmetric septal hypertrophy, either with or without left ventricular outflow tract obstruction, to moderate left ventricular dilation with or without apical aneurysm formation and marked, end-stage dilation with refractory heart failure. Sudden cardiac death can occur at any stage. The phenotypic variability observed in HCM is the end-result of many factors, including pre-load, after-load, wall stress and myocardial ischemia stemming from microvascular dysfunction and thrombosis; however, tissue level inflammation to include leukocyte-derived extracellular traps consisting of chromatin and histones, apoptosis, proliferation of matrix proteins and impaired or dysfunctional regulatory pathways contribute as well. Our current understanding of the pathobiology, developmental stages, transition from hypertrophy to dilation and natural history of HCM with emphasis on the role of tissue-level inflammation in myocardial fibrosis and ventricular remodeling is summarized.

     

Novel approaches to retard ventricular remodeling in heart failure

While the etiologies of congestive heart failure (CHF) are diverse, a common event in the progression of this disease process is LV remodeling, increased wall stress, and subsequent pump dysfunction. Therapeutic approaches for CHF have been focused upon reducing LV afterload through vasodilator therapy, or by blocking/interrupting the effects of neurohormonal stimuli. However, another therapeutic approach would be to directly intervene in the LV remodeling process with CHF. An important determinant in the maintenance of myocyte shape, alignment and transduction of myocyte shortening into an overall ejection is the structural support provided by the fibrillar collagen matrix. As in most tissue remodeling processes, LV myocardial remodeling with CHF is accompanied by changes in the structure and composition of the collagen matrix. Matrix metalloproteinases (MMPs) are an endogenous family of zinc-dependent enzymes which have been identified to be responsible for matrix remodeling and alterations in MMP expression and activity have been identified in clinical and animal models of CHF. Moreover, alterations in the tissue inhibitors of MMPs (TIMPs) have also been identified to occur in the end-stage CHF myocardium. Thus, it is very likely that increased MMP activity and reduced inhibitory control of the TIMPs contribute to the LV remodeling process with CHF. A number of bioactive peptides and cytokines influence MMP and TIMP expression and activity. In addition, pharmacologically active MMP inhibitors have been synthesized and are currently under study. Accordingly, the control of MMP and TIMP expression and activity within the failing myocardium represents a new and potentially significant therapeutic target for CHF.     

Progressive left ventricular remodeling in patients with hypertrophic cardiomyopathy and severe left ventricular hypertrophy

OBJECTIVES: The aim of this study was to determine the natural history of patients with hypertrophic cardiomyopathy (HCM) and severe left ventricular hypertrophy (LVH) (i.e., maximal left ventricular wall thickness [MLVWT] >/=30 mm) and whether changes in cardiac morphology influence the course of the disease. BACKGROUND: Severe LVH is common in young and rare among elderly patients with HCM. This has been explained by a high incidence of sudden death. We hypothesized that this age-related difference might be explained by left ventricular wall thinning. METHODS: A total of 106 (age 33 +/- 15 years; 71 males) consecutive patients with severe LVH underwent history taking, examination, electrocardiography, echocardiography, cardiopulmonary exercise testing, and Holter analysis. Survival data were collected at subsequent clinic visits or by communication with patients and their general practioners. In order to assess morphologic and functional changes, 71 (67.0%) patients (mean age 31 +/- 15 years; 47 males) followed at our institution underwent serial (>/=1 year) assessment. RESULTS: Of the 106 patients, the majority (78 [71.6%]) were <40 years of age. During follow-up (92 +/- 50 months [range 1 to 169]), 18 (17.0%) patients died or underwent heart transplantation (13 sudden cardiac deaths, 2 heart failure deaths, 1 heart transplantation, 1 stroke, 1 postoperative death). Five-year survival from sudden death was 90.1% (95% confidence interval [CI] 84.0% to 96.3%), and that from heart failure death or transplantation was 97.7% (95% CI 94.5 to 100). In patients serially evaluated over 85 +/- 51 months, there was an overall reduction in MLVWT of 0.6 mm/year (95% CI 0.31 to 0.81, p = 0.00004). Wall thinning >/=5 mm was observed in 41 patients (57.7%; age 35 +/- 13 years; 28 males). On multivariate analysis, the follow-up duration only predicted wall thinning (0.6 mm/year, 95% CI 0.38 to 0.85, p < 0.00001). CONCLUSIONS: Left ventricular remodeling is common in patients with severe LVH and contributes to the low prevalence of severe LVH seen in middle age and beyond.     

Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy

To determine the effects of aging on the human myocardium, 67 hearts were obtained from individuals who died from causes other than cardiovascular disease. The age interval examined was 17-90 years. Regression analysis demonstrated that the aging process was characterized by a loss of 38 million and 14 million myocyte nuclei/yr in the left and right ventricular myocardium, respectively. This loss in muscle mass was accompanied by a progressive increase in myocyte cell volume per nucleus in both ventricles. Left ventricular myocytes enlarged by 110 microns3/yr, whereas right ventricular myocytes increased by 118 microns3/yr, resulting in a preservation of ventricular wall thickness. However, the cellular hypertrophic response was unable to maintain normal cardiac mass. Left and right ventricular weights decreased by 0.70 and 0.21 g/yr, respectively. In conclusion, loss of cells and enlargement of the remaining myocytes may represent the structural basis for the reduced compensatory capacity of the aged heart and together may contribute to the development of myocardial dysfunction and failure in the elderly.     

Surgical left ventricular remodeling in heart failure

The high mortality and morbidity of patients in terminal heart failure are a therapeutic challenge to modern medicine. Surgically, cardiac transplantation is an excellent treatment for many patients. However, lack of donors combined with an increasing number of patients has led to the search for other surgical strategies. Patients with symptomatic large left ventricular aneurysms have been treated with resection of the aneurysm and closure of the left ventricle either directly (linear closure, first reported by Cooley) or by implantation of a patch (endoventricular patch plasty or Dor procedure). Akinetic areas of the left ventricle have also been successfully treated by the latter method. According to the law of Laplace, large dilated ventricles have increased wall tension and thus increased oxygen consumption. Based on this fact, Batista and coworkers have reduced the volume of enlarged left ventricles in patients in terminal heart failure by removing a wedge of myocardium from the apex of the heart towards the base of the left ventricular free wall. Although a favorable outcome has been reported in selected patients, this method is currently not recommended for treatment of heart failure because of high surgical failure rates. The present paper reviews some of the relevant literature regarding surgical left ventricular remodeling in heart failure. Two new techniques (Myosplint and CorCap cardiac support device) are also briefly described.     

Getting to the heart of cardiac remodeling; how collagen subtypes may contribute to phenotype

The objective of this study was to investigate the nature and biomechanical properties of collagen fibers within the human myocardium. Targeting cardiac interstitial abnormalities will likely become a major focus of future preventative strategies with regard to the management of cardiac dysfunction. Current knowledge regarding the component structures of myocardial collagen networks is limited, further delineation of which will require application of more innovative technologies. We applied a novel methodology involving combined confocal laser scanning and atomic force microscopy to investigate myocardial collagen within ex-vivo right atrial tissue from 10 patients undergoing elective coronary bypass surgery. Immuno-fluorescent co-staining revealed discrete collagen I and III fibers. During single fiber deformation, overall median values of stiffness recorded in collagen III were 37±16% lower than in collagen I [p<0.001]. On fiber retraction, collagen I exhibited greater degrees of elastic recoil [p<0.001; relative percentage increase in elastic recoil 7±3%] and less energy dissipation than collagen III [p<0.001; relative percentage increase in work recovered 7±2%]. In atrial biopsies taken from patients in permanent atrial fibrillation (n=5) versus sinus rhythm (n=5), stiffness of both collagen fiber subtypes was augmented (p<0.008). Myocardial fibrillar collagen fibers organize in a discrete manner and possess distinct biomechanical differences; specifically, collagen I fibers exhibit relatively higher stiffness, contrasting with higher susceptibility to plastic deformation and less energy efficiency on deformation with collagen III fibers. Augmented stiffness of both collagen fiber subtypes in tissue samples from patients with atrial fibrillation compared to those in sinus rhythm are consistent with recent published findings of increased collagen cross-linking in this setting.     

Matrix metalloproteinase in left ventricular remodeling and heart failure

Accumulation of oxidized matrix between the endothelium and cardiac muscle, and endocardial endothelial dysfunction, are the hallmarks of congestive heart failure. The induction of oxidative stress, decrease in endothelial cell density, activation of matrix and disintegrin metalloproteinase, collagenolysis, and repression of cardiac inhibitor of metalloproteinase (CIMP) are associated with deposition of oxidized matrix. Studies that employ CIMP as genetic or proteomic therapeutic agent may improve the heart’s response to nitric oxide donors. Identification of major players involved in the control of oxidative and proteolytic stresses that ameliorate matrix deposition by integrin shading will help to develop strategies to prevent congestive heart failure.     

The aging heart and post-infarction left ventricular remodeling

Aging is a risk factor for heart failure, which is a leading cause of death world-wide. Elderly patients are more likely than young patients to experience a myocardial infarction (MI) and are more likely to develop heart failure following MI. The poor clinical outcome of aging in cardiovascular disease is recapitulated on the cellular level. Increase in stress exposure and shifts in signaling pathways with age change the biology of cardiomyocytes. The progressive accumulation of metabolic waste and damaged organelles in cardiomyocytes blocks the intracellular recycling process of autophagy and increases the cell's propensity toward apoptosis. Additionally, the decreased cardiomyocyte renewal capacity in the elderly, due to reduction in cellular division and impaired stem cell function, leads to further cardiac dysfunction and maladaptive responses to disease or stress. We review the cellular and molecular aspects of post-infarction remodeling in the aged heart, and relate them to the clinical problem of post-infarction remodeling in elderly patients.     

Left ventricular remodeling in the post-infarction heart: a review of cellular,molecular mechanisms,and therapeutic modalities

As more patients survive myocardial infarctions, the incidence of heart failure increases. After an infarction, the human heart undergoes a series of structural changes, which are governed by cellular and molecular mechanisms in a pathological metamorphosis termed “remodeling.” This review will discuss the current developments in our understanding of these molecular and cellular events in remodeling and the various pharmacological, cellular and device therapies used to treat, and potentially retard, this condition. Specifically, this paper will examine the neurohormonal activity of the renin–angiotensin–aldosterone axis and its molecular effects on the heart. The emerging understanding of the extra-cellular matrix and the various active molecules within it, such as the matrix metalloproteinases, elicits new appreciation for their role in cardiac remodeling and as possible future therapeutic targets. Cell therapy with stem cells is another recent therapy with great potential in improving post-infarcted hearts. Lastly, the cellular and molecular effects of left ventricular assist devices on remodeling will be reviewed. Our increasing knowledge of the cellular and molecular mechanisms underlying cardiac remodeling enables us not only to better understand how our more successful therapies, like angiotensin-converting enzyme inhibitors, work, but also to explore new therapies of the future.     

Apoptosis in heart failure and the senescent heart

The progressive loss of cardiac myocytes by apoptotic cell death has been discussed as an important pathogenic component in the failing myocardium as well in the aging heart. The degree to which apoptosis contributes to myocyte loss in these conditions, however, is a controversial issue. This review focuses on the regulation of apoptosis, evidence implicating apoptosis as a mechanism for the progression and development of heart failure, the role of apoptotic death in senescent cardiac dysfunction, as well as on the problems of detection of apoptosis.     

Distinct macrophage lineages contribute to disparate patterns of cardiac recovery and remodeling in the neonatal and adult heart

The mechanistic basis for why inflammation is simultaneously both deleterious and essential for tissue repair is not fully understood. Recently, a new paradigm has emerged: Organs are replete with resident macrophages of embryonic origin distinct from monocyte-derived macrophages. This added complexity raises the question of whether distinct immune cells drive inflammatory and reparative activities after injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult heart, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition is a key determinant of cardiac tissue repair. Using a genetic model of cardiomyocyte ablation, we demonstrated that neonatal mice expand a population of embryonic-derived resident cardiac macrophages, which generate minimal inflammation and promote cardiac recovery through cardiomyocyte proliferation and angiogenesis. During homeostasis, the adult heart contains embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by monocyte-derived macrophages that are proinflammatory and lacked reparative activities. Inhibition of monocyte recruitment to the adult heart preserved embryonic-derived macrophage subsets, reduced inflammation, and enhanced tissue repair. These findings indicate that embryonic-derived macrophages are key mediators of cardiac recovery and suggest that therapeutics targeting distinct macrophage lineages may serve as novel treatments for heart failure.There are numerous examples of seemingly contradictory reports claiming that inflammation is both harmful after injury and essential for tissue repair (1). This paradox is well established in models of cardiac injury. Macrophages within the infarcted heart not only drive robust inflammatory responses and pathological left ventricular (LV) remodeling but also are required for the resolution of inflammation and reparative activities, including angiogenesis (2). One proposed explanation for these findings suggests that distinct macrophage populations may mediate inflammatory (M1) and reparative (M2) macrophage behaviors (3). However, the exact identities of these proposed macrophages remain undefined.Paradigm shifting studies have revealed that tissue macrophages represent a heterogeneous population of cells derived from distinct developmental origins (4), including embryonic-derived and adult monocyte-derived subsets (5–8). Consistent with these observations, we have recently reported that the adult heart also contains embryonic-derived and monocyte-derived macrophages (9) with differing recruitment dynamics and gene expression profiles. Although details describing the tissue distribution of embryonic-derived macrophages and their relationship to traditional monocyte-derived macrophages are beginning to emerge, the critical issue of whether macrophages of distinct origin have unique inflammatory, reparative, and immunologic functions remains largely unexplored.Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult, offering an ideal context in which to examine these concepts. After surgical apical resection, cryoablation, or myocardial infarction, neonatal mice efficiently regenerate myocardium (10–13), a process that is dependent on macrophages (14). The precise identity of neonatal macrophages and their relationship to macrophages found in the adult heart is unknown. On the basis of these findings, we hypothesized that distinct macrophage lineages are present in the neonatal and adult heart and explain the repeated observation that the neonatal heart recovers LV structure and function after tissue injury, whereas the adult heart undergoes pathologic remodeling and does not fully recover function.To test these hypotheses, we established an in vivo mouse model of cardiomyocyte injury, using a diphtheria toxin receptor (DTR)-based system. This model provides a simple approach to delivering precise and titratable cardiomyocyte cell death at varying stages of development and also avoids unintended consequences of surgical thoracotomy, including systemic inflammation and cardiac fibrosis (15). Through a combination of flow cytometry, genetic lineage tracing techniques, and depletion studies, we demonstrate that neonatal mice contain a resident macrophage lineage that is derived from the embryo, produces minimal inflammation, and is required for cardiac repair through the promotion of coronary angiogenesis and myocardial proliferation. During homeostasis, the adult heart contained embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by proinflammatory monocytes and monocyte-derived macrophages, which have a limited capacity to promote cardiac repair and, instead, generate inflammation and oxidative stress. We further demonstrate that manipulation of distinct macrophage lineages improves the adult heart’s intrinsic capacity for cardiac repair.     

Estrogen modulation of left ventricular remodeling in the aged heart

OBJECTIVE: To investigate the effects of estrogen on left ventricle (LV) mass and collagen deposition, and on the expression of receptors for estrogen (ER alpha, ER beta) and Ang II (AT(2)R, AT(1)R) in the heart of aged female rats. METHODS: Aged ( approximately 12 months old) intact (n=7), ovariectomized plus placebo (OVX, n=7), and estrogen-replaced (E2, n=6) as well as young ( approximately 3 months old, n=4) female Sprague-Dawley rats were used in this study. After 1 month of treatment, the left ventricular weight/body weight ratio (LVW/BW), changes in myosin heavy chain expression (MHC), matrix metalloproteinase (MMP)-2 activity, the collagen I/III ratio, and the expression of ERs and Ang II receptors in the LV were evaluated. RESULTS: In aged rats, OVX increased LVW/BW associated with a higher expression of beta-MHC isoform, increased collagen I/III ratio, and decreased MMP-2 activity compared to intact rats. Furthermore, the OVX group had a decrease in ERs alpha and beta as well as AT(2)R but an increase in AT(1)R expression. Estrogen replacement prevented the effects of ovariectomy on heart remodeling as well as increased further expression of ER beta and decreased AT(1)R expression. CONCLUSION: Removal of ovarian hormones increased LV remodeling in the aged rat, which could be attenuated by estrogen replacement. Moreover, regulation of Ang II receptor expression could be a mechanism by which estrogen may modulate heart remodeling.     

Matricellular proteins in the heart: possible role during stress and remodeling

Matricellular proteins are extracellular matrix proteins that modulate cell-matrix interactions and cell function, and do not seem to have a direct structural role. The family includes tenascin-C (TN-C), tenascin-X (TN-X), osteonectin, osteopontin, thrombospondin-1 (TSP1) and thrombospondin-2 (TSP2). Expression of matricellular proteins is high during embryogenesis, but almost absent during normal postnatal life. Interestingly, it re-appears in response to injury. Left ventricular remodeling is a complicated process that occurs in the stressed heart, and is still not completely understood. Several members of the matricellular protein family, like tenascin-C, osteopontin, and osteonectin are up-regulated after cardiac injury. Therefore, this group of proteins may have crucial functions in the heart coping with stress. This review will focus on the expression, regulation and function of these matricellular proteins, and will discuss the crucial functions that these proteins might exert during remodeling of the stressed heart.     

阿托伐他汀对慢性心力衰竭大鼠左室重构和功能的影响及可能的机制

目的探讨阿托伐他汀对异丙肾上腺素(ISO)诱导的慢性心力衰竭(CHF)大鼠左室重构和心功能的影响以及可能的机制。方法将ISO诱导的CHF大鼠随机分成ISO组与ISO 阿托伐他汀组,同时以正常大鼠为对照组。4周后行心动超声、血流动力学、血清细胞因子检查和心脏标本检测(左室质量／体质量)及RT-PCR 检测心肌基质金属蛋白酶-2(MMP-2)mRNA表达水平。结果 (1)与对照组比较,ISO组左室收缩末期内径(LVESD)、左室舒张末期内径(LVEDD)、左室舒张末压(LVEDP)及左室压力最大下降速率(dp／dtmin)明显升高,左室收缩末压(LVESP)、左室压力最大上升速率(dp／dtmax)及左室短轴缩短率(FS)则明显降低(P<0．01);而ISO 阿托伐他汀组,LVESD、LVEDD、LVEDP、dp／dtmin和LVESP、dp／dtmax及FS值则介于对照组与ISO组之间,且与ISO组比较, LVESD、LVEDD、LVEDP及dp／dtmin明显降低,而LVESP、dp／dtmax及FS则明显升高(P<0．05);左室后壁厚度在 ISO组和ISO 阿托伐他汀组没有明显的不同(P>0．05)。(2)与对照组相比,ISO组和ISO 阿托伐他汀组左室质量／体质量(LVW／BW)明显增大(P<0．01);但与ISO组比较,ISO 阿托伐他汀组LVW／BW降低(P<0．05)。 ISO组MMP-2 mRNA表达水平较对照组明显升高(P<0．01),而ISO 阿托伐他汀组较ISO组降低(P<0．05)。 (3)ISO组大鼠血清肿瘤坏死因子-α(TNF-α)和白细胞介素-6(IL-6)水平均比正常对照组显著升高(P<0．01); 与ISO组比较,ISO 阿托伐他汀组血清TNF-α和IL-α水平明显降低(P<0．05)。结论阿托伐他汀通过降低ISO诱导的CHF大鼠细胞因子水平,从而改善左室重构及心脏功能。